Early liver and yolk sac cells (green) and early pancreas cells (orange) are visualized in an 8.5 day old mouse embryo (Zaret & Grompe, cover of Science Magazine, 2008).

Newly specified pancreatic progenitor cells (yellow) are seen in the early mouse embryo.

The goal of our laboratory is to understand ways that genes are regulated in order to allow one type of cell to change into another type of cell. Such “cell type control” occurs in embryonic development and tissue regeneration, when embryo or adult stem cells become specialized for tissue function. Understanding cell type control is crucial to being able to generate new cells at will for therapeutics and for generating experimental models to unveil the basis of, and cures for, human disease.

Discoveries:

We discovered special gene regulatory proteins that we called “pioneer factors,” which are among the first to bind to genes in embryonic development. We found that pioneer factors can recognize silent gene target sequences and loosen the local chromosomal structure, endowing the competence for genes to be activated at a later developmental stage. Pioneer factors are now being found in diverse contexts by other research groups, including in reprogramming cell fate and in enabling gene regulation by hormones in cancer cells.

We found that unspecialized stem cells in the embryo can contain a “pre-pattern” by which genes for different tissues are marked differently from one another, prior to the commitment of the stem cells to liver or pancreas fates. We also identified a dynamic signaling network that extends from the external cell environment to gene regulatory proteins and induces the decision to make liver or pancreas cells in the embryo. The information from these studies is now being used by diverse research groups to generate new liver cells and pancreatic insulin-producing cells from stem cells, for diabetics.

Recent studies from the laboratory have focused on the ability to convert one specialized type of cell into another. Such conversions, whether occurring in the laboratory or in human pathologies, are rare and highly inefficient. We discovered a chromosomal molecular barrier to the cell conversion process that is revealing information about the ways that cells stably maintain their specialized functions. By perturbing the chromosomal molecular barrier, we can enhance the conversion of one cell type into another. We anticipate that this approach will facilitate cell type conversions in various biomedical contexts.

Our laboratory has used stem cell technology to develop a new experimental model to understand and track early stages of human cancer. We created a stem cell-like line from human pancreatic cancer cells that can undergo the early stages of disease progression. This allowed us to identify a new regulatory network that is activated in the early stages of pancreatic cancer. We also used the system to discover secreted and released proteins from the early stage cancer cells that we are testing as new diagnostics in the clinic. Furthermore, the cells will allow us to test the role of anti-cancer drugs in combating pancreatic cancer at early stages, before the cells become metastatic.